title: Febuxostat, an inhibitor of xanthine oxidase, suppresses lipopolysaccharide-induced MCP-1 production via MAPK phosphatase-1-mediated inactivation of JNK.
abstract: Excess reactive oxygen species (ROS) formation can trigger various pathological conditions such as inflammation, in which xanthine oxidase (XO) is one major enzymatic source of ROS. Although XO has been reported to play essential roles in inflammatory conditions, the molecular mechanisms underlying the involvement of XO in inflammatory pathways remain unclear. Febuxostat, a selective and potent inhibitor of XO, effectively inhibits not only the generation of uric acid but also the formation of ROS. In this study, therefore, we examined the effects of febuxostat on lipopolysaccharide (LPS)-mediated inflammatory responses. Here we show that febuxostat suppresses LPS-induced MCP-1 production and mRNA expression via activating MAPK phosphatase-1 (MKP-1) which, in turn, leads to dephosphorylation and inactivation of JNK in macrophages. Moreover, these effects of febuxostat are mediated by inhibiting XO-mediated intracellular ROS production. Taken together, our data suggest that XO mediates LPS-induced phosphorylation of JNK through ROS production and MKP-1 inactivation, leading to MCP-1 production in macrophages. These studies may bring new insights into the novel role of XO in regulating inflammatory process through MAPK phosphatase, and demonstrate the potential use of XO inhibitor in modulating the inflammatory processes.
authors.affiliation: Pharmaceutical Department Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Hino, Tokyo, Japan.
authors.forename: Johji
authors.initials: J
authors.lastname: Nomura
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
authors.forename: Annette
authors.initials: A
authors.lastname: Ives
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Tsujimoto
authors.forename: Mizuho
authors.initials: M
authors.lastname: Tamura
authors.forename: Alexander
authors.initials: A
authors.lastname: So
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamanaka
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D000069465:Febuxostat; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013844:Thiazoles; D000069465:Febuxostat; D014969:Xanthine Oxidase; D048670:MAP Kinase Kinase 4; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1